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Diindolylmethane formulations for the treatment of leiomyomas

a technology of diindolylmethane and formulations, which is applied in the field of diindolylmethane formulations for the treatment of leiomyomas, can solve the problems of pelvic discomfort, bowel and bladder dysfunction, and the pathobiology of leiomyomas remains poorly understood, and achieves the effect of increasing the efficacy

Active Publication Date: 2005-12-01
BIORESPONSE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0027] In yet another embodiment, combination therapy for leiomyomas, included within the scope of this invention, includes the use of DIM and DIM-related compounds used with and without EGFR antagonists in conjunction with Uterine Artery Embolization (UAE), surgical myomectomy, and / or low-dose external beam radiation therapy. The object of combined use of DIM and DIM-related compounds with other treatment modalities for leiomyomas is to increase the efficacy over a single modality therapy alone.

Problems solved by technology

Despite their frequency, the pathobiology of leiomyomas remains poorly understood.
Leiomyomas may also cause pelvic discomfort, and bowel and bladder dysfunction from pressure on these adjacent structures.
The presence of leiomyomas can interfere with normal labor during the birth process, necessitating cesarean section.
In addition to abnormal labor, leiomyomas restrict normal intra-uterine growth and predispose to postpartum hemorrhage secondary to uterine atony.
Other than surgery, there are few safe and effective treatment options available to women with symptomatic leiomyomas.
However, because these agents cause severe menopausal symptoms and the risk of estrogen-deficiency related bone loss (osteoporosis), these drugs cannot be used for prolonged periods of time.
Moreover, leiomyomas tend to regrow after cessation of GNRH-a therapy.
As a result, GnRH-a treatment, independent of subsequent surgery, is not recognized as an effective, long-term treatment of leiomyomas.
Unfortunately, myomectomy is followed by extensive pelvic adhesions that themselves can reduce future fertility.
Additionally, if the leiomyoma penetrates the uterine cavity, any future pregnancy after myomectomy carries an increased risk of uterine rupture and delivery has to be accomplished by cesarean section.
The impact of this surgical approach to leiomyomas is extremely costly considering the long postoperative time and recuperation away from work.
There are also well known complications to hysterectomy.
The procedure is also not recommended for women who wish to get pregnant, since the risk of uterine rupture is high.
However, acutely causing the death of myoma tissue due to arterial blockage has side effects.
Some concern about future fertility has been raised following UAE, as well as lack of ability to treat all leiomyomas present.
However, I3C is highly unstable in water and acid.
In addition, unwanted enzyme induction by I3C reaction products following oral I3C use may alter the metabolism of other drugs, steroid hormones including estrogen, and contraceptives raising safety concerns.
In addition, I3C's use is associated with a number of safety concerns due to its enzyme-inducing and reproductive-toxic actions making it unacceptable for use in women of reproductive age (Dashwood, 1998, Chem Biol Interact.

Method used

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  • Diindolylmethane formulations for the treatment of leiomyomas
  • Diindolylmethane formulations for the treatment of leiomyomas
  • Diindolylmethane formulations for the treatment of leiomyomas

Examples

Experimental program
Comparison scheme
Effect test

example 1

6. EXAMPLE 1

Manufacture of an Absorption-Enhanced Formulation of Dim for Treated of Leiomyomas

[0120] In general, a suitable (therapeutically effective) amount of diindolylmethane is preferably administered in an absorption enhancing formulation, as described in U.S. Pat. No. 6,086,915, at 100-2000 mg per day as a suspension of microparticles in a starch carrier matrix. The actually administered amounts of Diindolylmethane may be decided by a supervising physician.

[0121] Preparation of processed Diindolylmethane was accomplished according to the steps outlined in U.S. Pat. No. 6,086,915, herein incorporated by reference in its entirety. Briefly, this included mixture of about 10-40% by final weight of either diindolylmethane with about 10-40% by final weight of vitamin E polyethylene glycol 1000 succinate (Vitamin-E-TPGS, Eastman Chemical), 2-20% by final weight, phosphatidyl choline (Phospholipon 50G, Rhone Poulenc) and 15-30% by final weight hexanol. This mixture was made homogen...

example 2

7. EXAMPLE 2

Manufacture of Capsules Containing Diindolylmethane

[0123] Capsules containing 150-300 mg of processed diindolylmethane, as produced according to the steps described in Example 1, were made by mixing the processed diindolylmethane with microcrystaline cellulose and placing the mixed powder into opaque gelatin capsules.

[0124] Alternatively, capsules containing processed diindolylmethane (DIM), as produced according to the steps described in Example 1, were made by mixing the processed DIM with polyphenolic EGFR inhibitory compounds according to the following per capsule amounts. The ingredients are mixed according to these amounts and capsules are filled using standard machinery.

TABLE 5Preferred CapsuleRange of CapsuleComponentWeight (mg)Weight (mg)Processed DIM 75 (50-100)Silibinin (SiliPhos)100(100-200)Green Tea Extract (EGCG)150(150-300)Total Active Fill Weight (mg)325(300-625)

[0125] Optionally, 6-25 mg of Lycopene is added to each capsule and / or 25-100 mg of Scutel...

example 3

8. EXAMPLE 3

Manufacture of a Vaginal Suppository Formulation of Dime for Treatment of Leiomyomas in Conjuction with Oral Therapy

[0126] In a heated vessel, 90 grams cetostearyl alcohol (Alfol 16 / 18, Vista) was heated to 100° C. to which 5 gms of microcrystalline DIM (LKT Labs, St. Paul, Minn.) was added with constant mixing to form a hot slurry. Alternatively, 90 grams cetostearyl alcohol (Alfol 16 / 18, Vista) is heated to 100° C. to which 5 gms of microcrystalline DIM is mixed, alone or together with 10 grams of ceramide or synthetic cerimide derivatives, C2 ceramide. In a second vessel 400 gms of IV Novata (Semi-synthetic Glyceride Suppository Base, Ashland Chemicals) was warmed to 40° C. with constant mixing. The well mixed slurry from the first vessel was added with continued mixing to the second vessel. The homogenized molted suppository material was formed into suppositories of 2 gms each and cooled. Glyceryl monsterate 10-50 gms was added to the molten mixture as needed to inc...

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Abstract

The present invention relates to compositions and methods for treating or preventing leiomyomas by administration of diindolylmethane and diindolylmethane-related indole. The present invention also relates to compositions and methods for treating or preventing leiomyomas by administration of diindolylmethane in combination with an EGFR antagonist. The methods provide non-invasive treatments for leiomyomas.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 569,478, filed on May 6, 2004, which is incorporated herein by reference in its entirety.1. FIELD OF THE INVENTION [0002] The present invention relates to compositions and methods for treating or preventing leiomyomas by administration of diindolylmethane or a diindolylmethane-related indole. The present invention also relates to compositions and methods for treating or preventing leiomyomas by administration of diindolylmethane or a diindolylmethane-related indole in combination with an EGFR antagonist. The methods provide non-invasive treatments for leiomyomas. 2. BACKGROUND OF THE INVENTION [0003] 2.1. Clinical Importance of Uterine Leiomyomas [0004] Leiomyomas are benign soft-tissue tumors that arise from smooth muscle tissue. Leiomyomas of the uterus are the most common, abnormal pelvic growth diagnosed in women. Leiomyomas are also called “myomas” and “uterine fibroids”. As benign, non-cancerous, gr...

Claims

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Application Information

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IPC IPC(8): A61K31/404
CPCA61K31/404
Inventor ZELIGS, MICHAEL A.
Owner BIORESPONSE
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